title: Structural basis for S-adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1.
abstract: Eukaryotic transcription factor B (TFB) proteins are homologous to KsgA/Dim1 ribosomal RNA (rRNA) methyltransferases. The mammalian TFB1, mitochondrial (TFB1M) factor is an essential protein necessary for mitochondrial gene expression. TFB1M mediates an rRNA modification in the small ribosomal subunit and thus plays a role analogous to KsgA/Dim1 proteins. This modification has been linked to mitochondrial dysfunctions leading to maternally inherited deafness, aminoglycoside sensitivity and diabetes. Here, we present the first structural characterization of the mammalian TFB1 factor. We have solved two X-ray crystallographic structures of TFB1M with (2.1 Å) and without (2.0 Å) its cofactor S-adenosyl-L-methionine. These structures reveal that TFB1M shares a conserved methyltransferase core with other KsgA/Dim1 methyltransferases and shed light on the structural basis of S-adenosyl-L-methionine binding and methyltransferase activity. Together with mutagenesis studies, these data suggest a model for substrate binding and provide insight into the mechanism of methyl transfer, clarifying the role of this factor in an essential process for mitochondrial function.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA, Medical Scientist Training Program, Stony Brook University Medical Center, Stony Brook, NY 11794, USA and Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Kip E
authors.initials: KE
authors.lastname: Guja
authors.forename: Krithika
authors.initials: K
authors.lastname: Venkataraman
authors.forename: Elena
authors.initials: E
authors.lastname: Yakubovskaya
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.forename: Edison
authors.initials: E
authors.lastname: Mejia
authors.forename: Elena
authors.initials: E
authors.lastname: Hambardjieva
authors.forename: A Wali
authors.initials: AW
authors.lastname: Karzai
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia-Diaz
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008780:Methyltransferases / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D012436:S-Adenosylmethionine / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D024101:Mitochondrial Proteins; C499632:TFB1M protein, human; C462441:Tfb1m protein, mouse; D014157:Transcription Factors; D012436:S-Adenosylmethionine; D008780:Methyltransferases; C047346:16S rRNA (adenine(1518)-N(6)-adenine(1519)-N(6))-dimethyltransferase